2. Academic Validation
  3. CSTF2-impeded innate αβ T cell infiltration and activation exacerbate immune evasion of pancreatic cancer

CSTF2-impeded innate αβ T cell infiltration and activation exacerbate immune evasion of pancreatic cancer

  • Cell Death Differ. 2025 Feb 19. doi: 10.1038/s41418-025-01464-0.
Xiaowei He # 1,  Ji Liu # 1,  Yifan Zhou # 1,  Sihan Zhao # 1,  Ziming Chen 1,  Zilan Xu 1,  Chunling Xue 1,  Lingxing Zeng 1,  Shuang Liu 1,  Shaoqiu Liu 1,  Ruihong Bai 1,  Shaojia Wu 1,  Lisha Zhuang 1,  Mei Li 2,  Hongzhe Zhao 1,  Quanbo Zhou 3,  Dongxin Lin 1 4 5,  Jian Zheng 6 7 8,  Xudong Huang 9,  Jialiang Zhang 10
Affiliations

Affiliations

  • 1 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China.
  • 2 Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 3 Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China.
  • 4 Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 5 Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China.
  • 6 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China. zhengjian@sysucc.org.cn.
  • 7 Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China. zhengjian@sysucc.org.cn.
  • 8 Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China. zhengjian@sysucc.org.cn.
  • 9 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China. huangxd@sysucc.org.cn.
  • 10 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China. zhangjial@sysucc.org.cn.
  • # Contributed equally.
PMID: 39972059 DOI: 10.1038/s41418-025-01464-0
Abstract

Alternative cleavage and polyadenylation (APA) have gained increasing attention in Cancer biology, yet its role in modulating anti-tumor immune response remains largely unexplored. Here, we identify the cleavage stimulation factor 2 (CSTF2), an APA-related gene, as a pivotal suppressor of anti-tumor immunity in pancreatic ductal adenocarcinoma (PDAC). CSTF2 promotes tumor development by inhibiting the infiltration and cytotoxic immune cell recruitment function of TCRαβ+CD4-CD8-NK1.1- innate αβ T (iαβT) cells. Mechanistically, CSTF2 diminishes CXCL10 expression by promoting PolyA polymerase alpha (PAPα) binding to the 3' untranslated regions of CXCL10 RNA, resulting in shortened PolyA tails and compromised RNA stability. Furthermore, we identify Forsythoside B, a selective inhibitor targeting the RNA recognition motif of CSTF2, can effectively activate anti-tumor immunity and overcome resistance to Immune Checkpoint blockade (ICB) therapy. Collectively, our findings unveil CSTF2 as a promising therapeutic target for sensitizing PDAC to ICB therapy.

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